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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Derangements in coagulation and fibrinolysis are frequent complications of systemic infection, and septic shock is the most common recognized cause of disseminated intravascular coagulation. Anticoagulant therapy has been used as a treatment strategy for severe sepsis for several decades without compelling evidence of efficacy until the 2001 publication of the phase III trial with recombinant human activated protein C. Major phase III international trials with antithrombin and tissue factor pathway inhibitor also have been completed recently. The molecular mechanisms by which the clotting system interacts with the innate immune response have greatly facilitated the understanding of coagulation and the pathophysiology of septic shock. Anticoagulants such as recombinant human activated protein C and related agents may become the mainstay of adjuvant therapies for severe sepsis in the near future.
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PMID:Clinical impact of novel anticoagulation strategies in sepsis. 1180 32

The rejection of xenografts is associated with vascular-based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve into disseminated intravascular coagulation. Natural regulators of coagulation in porcine xenografts have abnormal physiological interaction with human effectors. We have demonstrated the enhanced potential of porcine von Willebrand factor to associate with human platelet GPlb to be dependent upon the isolated AI domain of von Willebrand factor. The inability of porcine tissue factor pathway inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant activation of both human prothrombin and FXa by porcine EC and the failure of the porcine natural anticoagulant, thrombomodulin to bind human thrombin and hence activate human protein C may all be pathogenetic in the DIC following xenograft rejection. In this brief review, molecular incompatibilities of contributors in the physiologically fine tuned system of hemostasis are summarized and brought in context with the disordered thromboregulation, that seems to be invariably associated with delayed xenograft rejection. Possible therapeutic interventions are discussed.
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PMID:Molecular incompatibilities in hemostasis between swine and men--impact on xenografting. 1189 92

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) are critically involved in activation of the coagulation system in sepsis, leading to disseminated intravascular coagulation (DIC). Natural anticoagulants such as antithrombin (AT) and activated protein C (APC) regulate the coagulation system by inhibiting thrombin generation. In addition to these anticoagulant effects, both AT and APC have been shown to attenuate inflammatory responses induced by various noxious stimuli in rats such as lipopolysaccharide (LPS) challenge. AT promotes the endothelial release of prostacyclin, a potent anti-inflammatory prostaglandin that inhibits the monocytic production of TNF-alpha, by interacting with cell-surface heparin-like substances. APC directly inhibits the production of TNF-alpha by inhibiting the activation of both nudear factor kappaB (NFkappaB) and activator protein-1 in monocytes stimulated with LPS. Thrombomodulin, an endothelial membranous integral protein that binds thrombin, exerts anti-inflammatory effects by generating APC. Furthermore, tissue factor pathway inhibitor, a natural anticoagulant for the extrinsic pathway of the coagulation system, also attenuates LPS-induced inflammatory responses in rats by inhibiting TNF-alpha production by monocytes. These findings strongly suggest that natural anticoagulants could regulate inflammatory responses as well as the coagulation system in rats by inhibiting the monocytic production of TNF-alpha. Such anti-inflammatory properties of natural anticoagulants are potentially important for their replacement in patients with sepsis who frequently develop DIC and organ failure as inflammatory responses.
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PMID:Regulation of inflammatory responses by natural anticoagulants. 1191 84

Changes of hemostatic markers in 226 patients with disseminated intravascular coagulation (DIC) and hematopoietic disorders were examined after treatment of DIC. The changes in prothrombin time (PT) ratio, fibrinogen, fibrin and fibrinogen degradation products (FDP), antithrombin, and protein C, thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), and soluble fibrin monomer complex (SFMC) in all patients with DIC were significant during the clinical course of DIC, but those of D-dimer, thrombomodulin (TM), tissue factor (TF), and tissue factor pathway inhibitor (TFPI) were not. Activated partial thromboplastin time (aPTT) and PT were significantly longer in the poor response group than in good response group. Plasma levels of FDP, TAT, PPIC, SFMC, TM, and DIC score were significantly higher in poor response group than in good response. Protein C and antithrombin levels were significantly lower in poor response group than in good response group. The changes of PT ratio, fibrinogen, FDP, DIC score, antithrombin, plasmin inhibitor, and protein C were significant in the good response group, but these levels were not significant in the poor response group. The changes in plasma TAT and SFMC levels were significant in the good response group but were not in poor response group. The changes in D-dimer, TM, TF, or TFPI were not significant in both groups. These findings suggest that anticoagulant agents should be administered at levels below TAT 40 ng/mL or SFMC 300 microgram/mL in patients with DIC and hematopoietic disorders.
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PMID:Good or poor responses of hemostatic molecular markers in patients with hematopoietic disorders after treatment of disseminated intravascular coagulation. 1264 27

PURPOSE: To discuss the current rationale for the use of specific and nonspecific therapies for thrombotic microangiopathy in thrombocytopenia-associated pediatric multiple organ failure syndromes. Methods: Pertinent PubMed and MEDLINE citations and proceedings of recent critical care meeting presentations were reviewed. RESULTS: Critical care clinicians have reported using antithrombin III concentrate, protein C concentrate, activated protein C, prostacyclin and its analogues, heparin, tissue factor pathway inhibitor concentrate, plasma infusion, plasma exchange, whole blood exchange, pentoxifylline, tissue plasminogen activator, urokinase, and streptokinase with perceived therapeutic benefits in patients with thrombocytopenia-associated multiple organ failure, including those with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, disseminated intravascular coagulation syndrome, and secondary thrombotic microangiopathy syndrome without prolonged prothrombin time/activated partial thromboplastin time. CONCLUSION: Assuming that underlying disease is remediable, a consensus has developed that thrombotic microangiopathy is a therapeutic target in children with thrombocytopenia-associated multiple organ failure syndromes. Studies are warranted to delineate efficacious use of specific and nonspecific therapies to prevent and reverse thrombotic microangiopathy in these patients.
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PMID:Microvascular thrombosis in pediatric multiple organ failure: Is it a therapeutic target? 1279 40

This review describes disseminated intravascular coagulation (DIC) as a syndrome in which hemostatic factors are activated. The syndrome ranges in severity from a decompensated coagulopathy (overt-DIC) to the subclinical compensated activation of hemostatic factors (nonovert DIC). The first part of this review emphasizes two points. First, activation of the hemostatic system is controlled by a vast network of capillaries and venules through anticoagulant and anti-inflammatory regulatory factors that operate from the endothelium (e.g., protein C and thrombomodulin, tissue factor pathway inhibitor). These hemostatic regulators can be overridden by procoagulant disorders such as amniotic fluid embolism or degraded by proinflammatory disorders such as sepsis. Second, because this link between the microvascular endothelium and circulating hemostatic factors is so close, even a relatively mild disturbance of the microvasculature targeted by the inflammatory process may be reflected systemically by changes in molecular biomarkers of hemostatic activity. Therefore, application of criteria for the diagnosis of nonovert DIC should be of value in detecting a compensated response to inflammatory stress of the microvasculature in patients who are at risk before they develop an uncompensated over DIC response and organ failure. The second part of this review covers the recent experience investigators have had in diagnosing and following the response of patients to treatment with biomarkers.
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PMID:The diagnosis and management of disseminated intravascular coagulation. 1290 Nov 23

Hypercoagulability is widely associated with sepsis, inflammation, diabetes, cancers, aging, and many pathological conditions, resulting in life-threatening disseminated intravascular coagulation (DIC), venous thrombosis, thromboembolism, cardiovascular complications, or even deadly multiple organ failure. Relieving coagulation dysfunction is not only a task for research scientists but also a challenge for physicians. The development of effective anticoagulants is under way with the basic understanding of the pathophysiology of hypercoagulable state. In this overview, various anticoagulants will be discussed according to the proposed inhibitory target-sites along the extrinsic pathway that is believed to play an integral role in homeostasis. Anticoagulants generally fall into two broad categories as natural or pharmacological ones. Antithrombin (AT), activated protein C (APC), and tissue factor pathway inhibitor (TFPI) mainly constitute the natural anticoagulant system apart from the recently reported physiological components such as lipoproteins, sphingosine, thrombomodulin (TM) or cellular Marcks protein. Pharmacological anticoagulants include warfarin, FVIIa inhibitors, FXa inhibitors, and thrombin inhibition by its direct inhibitors or heparins. In addition, a group of novel compounds inhibiting TF-dependent FVII activation result in anticoagulation; such upstream downregulation in the extrinsic pathway awaits further research to establish their in vivo benefits. The molecular genetic approaches such as developing soluble TF, FVII and thrombin mutants provide unique downregulation. Anticoagulation also extends its significance to anti-inflammation, making broad impacts on the improvement of human health.
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PMID:Biochemical strategies to anticoagulation: a comparative overview. 1532 Aug 20

The biochemical mechanisms by which activated platelets participate in exposing receptors for the assembly of enzyme-cofactor-substrate complexes at all stages of the blood coagulation cascade are reviewed. Information derived from studies conducted during the last 30 years supports the concept that the initiation of blood coagulation is triggered by exposure of tissue factor at injury sites, leading to the generation of minute quantities of thrombin (limited by tissue factor pathway inhibitor), sufficient to activate platelets, factors XI, VIII, and V, and trigger the consolidation pathway (i.e., the sequential activation of factors XI, IX, X, and prothrombin on the activated platelet surface), leading to the generation of sufficient thrombin to convert fibrinogen to fibrin and effect hemostasis. Platelets localize coagulation to the hemostatic thrombus and protect coagulation enzymes from inhibition by both plasma and platelet inhibitors (e.g., protease nexin 2), thus preventing disseminated intravascular coagulation.
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PMID:Platelet coagulation-protein interactions. 1535 67

Blood coagulation is a complex physiological process. With the development of biochemistry and molecular biology, especially the discovery of the tissue factor pathway inhibitor (TFPI) and further research, the researches of tissue factor (TF) and TFPI have been the hot topics now. Based on this result, we provide a new concept of blood coagulation system and provide a dynamic model to describe the role of TFPI of this pathway. Through stability analysis of the equilibrium point and numerical simulations, we obtain some important conclusions. All these results may have great significance for lesions of cardiac vessels and cerebral vessels, haemophilia, DIC, thrombosis formation and malignancy.
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PMID:Simulation of a mathematical model of the role of the TFPI in the extrinsic pathway of coagulation. 1576 16

Tissue factor pathway inhibitor (TFPI) is a physiological inhibitor of extrinsic pathway of coagulation and has biological functions of anticoagulation and anti-inflammation. Although TFPI has been proved to be a good therapeutic agent of sepsis, inflammatory shock, and DIC, the clinical application and therapeutic effects of TFPI are impeded because of its short half-life in vivo. In order to prolong the half-life of TFPI, homology modeling and molecule docking were performed on a computer workstation principally in protein structural biology and binding characteristics between TFPI and its receptor LRP (low-density lipoprotein receptor related protein). Two recombinant long half-life human TFPI mutants coined TFPI-Mut1 and TFPI-Mut4 were designed and expressed in E.coli. In comparison with the wild-type TFPI, TFPI-Mut1 and TFPI-Mut4 presented a few of changes in spatial configuration and a decrease in relative Gibbs free energy of docking complex by 17.3% and 21.5%, respectively, as indicated by a computer simulation. After refolding and purification, anticoagulant activities, anti-TF/FVIIa and anti-FXa activities of the mutants were found to be the same as those of wide-type TFPI. The pharmacokinetics research indicated that alpha phase half-life (t1/2 alpha) of TFPI-Mut1 and TFPI-Mut4 were prolonged 1.33-fold and 1.96-fold respectively, beta phase half-life (t1/2 beta) of TFPI-Mut1 and TFPI-Mut4 were prolonged 1.62-fold and 4.22-fold respectively. These results suggested that TFPI-Mut1 and TFPI-Mut4 maintained the bioactivities of wild-type TFPI, prolonged half-life in vivo simultaneously and were expected for better clinical value and therapeutic effect.
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PMID:Molecular design and characterization of recombinant long half-life mutants of human tissue factor pathway inhibitor. 1596 88


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